CHD4

protein-coding

chromodomain helicase DNA binding protein 4, the group of NuRD complex subunits|Small nucleolar RNA protein coding host genes|PHD finger proteins

Gene summary

The product of this gene belongs to the SNF2/RAD54 helicase family. It represents the main component of the nucleosome remodeling and deacetylase complex and plays an important role in epigenetic transcriptional repression. Patients with dermatomyositis develop antibodies against this protein. Somatic mutations in this gene are associated with serous endometrial tumors. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2014]

MANE transcript

NM_001273.5

Inheritance

ClinVar variants

P:88U:466B:209

Top phenotype

Sifrim-Hitz-Weiss syndrome

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr12:6,570,082-6,614,524

External References & Databases

Ensembl (ENSG00000111642)

Transcript & Mutation Effects

hg38 • Region Span ~44.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Sifrim-Hitz-Weiss syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014946

Submitter: G2P

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

*CHD4* was first reported in relation to autosomal dominant syndromic intellectual disability in 2016 (Sifrim et al., PMID: 27479907; Weiss et al., PMID: 27616479); the terms *CHD4* neurodevelopmental disorder and Sifrim-Hitz-Weiss syndrome have also been used in the literature to describe patients with *CHD4* variants. *CHD4* encodes a chromodomain-helicase DNA-binding protein that is involved in chromatin remodeling, epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Affected individuals present with motor and speech delays, mild-to-moderate intellectual disability, brain anomalies, heart defects, and dysmorphic facial features; other variable features include hypotonia, hearing loss, hypogonadotrophic hypogonadism in males, limb or skeletal anomalies, and Moyamoya angiopathy (PMIDs: 31388190, 31474762). Multiple patients with loss-of-function or missense variants in *CHD4* have also been reported to have congenital heart disease, including 65% in one report (PMID 31388190). Twenty-three unique variants (22 missense, 1 inframe indel) reported in 24 probands in 3 publications (PMIDs: 27616479, 31388190, 31474762) are included in this curation; 1 recurrent missense variant (p.Arg1127Gln) was reported in 2 unrelated probands. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Most variants are *de novo*. The mechanism of disease is suggested to be dominant negative or gain-of-function (PMID: 31388190). Four patients with protein truncating variants have also been reported (PMIDs: 31388190, 31474762), but were not scored in this curation due to lack of consistent clinical features and unclear disease mechanism. Additional genetic evidence is needed to determine whether loss of function is a mechanism of pathogenicity. *CHD4* is highly constrained for both missense (Z = 6.34, gnomAD v2.1.1) and loss-of-function variants (pLI = 1). This gene-disease relationship is also supported by experimental evidence, including *in vitro* functional assays, biochemical function, protein interaction, and cell culture models (PMIDs: 31388190, 29795351, 30409903, 32647123). Patient variants result in decreased ATPase and nucleosome remodeling activity (PMID: 31388190). In summary, there is definitive evidence supporting the relationship between *CHD4* and autosomal dominant syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 19, 2023 (SOP Version 9). In January 2026, this record underwent administrative updates to add a sentence to the evidence summary outlining the incidence of congenital heart defects and recognizing the Congenital Heart Disease GCEP as a secondary contributor.

Sifrim-Hitz-Weiss syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014946

Submitter: Ambry Genetics

Sifrim-Hitz-Weiss syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014946

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Sifrim-Hitz-Weiss syndromeAD

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic

Intervention: Audiologic/Otolaryngologic; Cardiovascular

Rationale: Among other features, the condition can include hearing loss, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 21743468; 27479907; 27616479

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHD4 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 562

Sifrim-Hitz-Weiss syndromeTotal: 132

Inborn genetic diseasesTotal: 126

not specifiedTotal: 117

CHD4-related disorderTotal: 98

Moyamoya angiopathy with developmental delayTotal: 7

CHD4-related disordersTotal: 4

Intellectual disabilityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001273.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			16 clinvar	140 clinvar	15 clinvar	171
missense	12 clinvar	59 clinvar	398 clinvar	48 clinvar	5 clinvar	522
nonsense		4 clinvar	11 clinvar			15
start loss			1 clinvar			1
frameshift	1 clinvar	4 clinvar	13 clinvar			18
splice donor/acceptor (+/-2bp)		8 clinvar	27 clinvar	1 clinvar		36
Total	13	75	466	189	20	763

Highest pathogenic variant AF is 0.000014263636

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 73 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001273.5	RefSeq	NP_001264.2	39	MANE Select
ENST00000544040.7	Ensembl	ENSP00000440542.2	39	MANE Select
NM_001297553.2	RefSeq	NP_001284482.1	39	Standard
NM_001363606.2	RefSeq	NP_001350535.1	39	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Viral carcinogenesis - Homo sapiens (human)
Human papillomavirus infection - Homo sapiens (human)
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression
Positive epigenetic regulation of rRNA expression
Signal Transduction

Biological Process

regulation of transcription by RNA polymerase II
histone deacetylation
DNA duplex unwinding
ATP-dependent chromatin remodeling

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
RNA polymerase II distal enhancer sequence-specific DNA binding
RNA polymerase II repressing transcription factor binding
DNA binding
ATP-dependent DNA helicase activity

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
cytoplasm
centrosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357008
Coding exons: 39
Length: 37394
Individuals with no LoFs: 125724
Homozygous LoFs: 0
Heterozygous LoFs: 24
Defined: 125748
p: 0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	6.34	504	1.09e+3	0.461	0.0000644	12640
Missense (PolyPhen)		120	381.01	0.31495		4232
Synonymous	-0.523	400	387	1.03	0.0000205	3564
Loss of Function	8.76	10	108	0.0922	0.00000659	1221

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0.00017	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin by deacetylating histones. {ECO:0000269|PubMed:17626165, ECO:0000269|PubMed:9804427}.;
Disease: DISEASE: Sifrim-Hitz-Weiss syndrome (SIHIWES) [MIM:617159]: An autosomal dominant syndrome characterized by mental retardation, variable congenital defects affecting cardiac, skeletal, and urogenital systems. Short stature, macrocephaly, hearing impairment, and facial dysmorphism are present in some patients. {ECO:0000269|PubMed:27479907, ECO:0000269|PubMed:27616479}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.318

Intolerance Scores

LoFtool: 0.0568
RVIS EVS: -1.64
RVIS percentile EVS: 2.82

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Indispensability pred.: E
Indispensability score: 0.979

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium